MART-1 Peptides、MART-1肽

Definition

MART-1 (melanoma antigen recognized by T-cells) is an antigen expressed by melanoma cells. Antibodies against the antigen are used in the medical specialty of anatomic pathology in order to recognize cells of melanocytic differentiation, useful for the diagnosis of a melanoma.

Discovery

MART-1 was discovered by two groups of researchers who independently sequenced the gene for this antigen in 1994. Both names are currently in common use. Kawakami et al., at the National Cancer Institute coined the term MART-1, which stands for "Melanoma Antigen Recognized by T-cells." Coulie et al., of Belgium called the gene Melan-A, an abbreviation for "melanocyte antigen." MART-1 is a widely shared melanoma antigen recognized by the T lymphocytes of patients with established malignancy 1, 2. In the case of melanoma, MART-1 has lineage-specific protein expressed in ~75–100% of primary and metastatic melanomas depending on their clinical stage 3.

Structural Characteristics

MART-1 gene is 18 kb long and comprises five exons. MART-1 is a transmembrane protein consisting of 118 amino acids. It has a single transmembrane domain 2. Two overlapping epitopes spanning amino acid residues 26 through 35 are of particular interest: numerous clinical studies have been performed using variants of the MART-1 26–35 decamer, although only the 27–35 nonamer has been found on the surface of targeted melanoma cells 4. The crystallographic structures of the various MART-126/27–35 nonamers and decamers indicate that there are two general conformational classes available to these peptides: an extended conformation adopted by the nonamers, and a bulged conformation adopted by the decamers and  nonamers.

Mode of Action

In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely used as clinical vaccines. Numerous clinical studies have been performed using variants of the MART-1 26–35 decamer. 26–35 and 27–35 peptides of MART-1 strikingly adopt different conformations when bound to HLA-A2. Clonally distinct MART-126/27–35-reactive T cells show broad cross-reactivity towards these ligands. Many of the cross-reactive T cells remain unable to recognize anchor-modified variants with very subtle structural differences. Findings also indicate that for design of immunotherapeutics based on the MART-1 26/27–35 epitopes, as neither cross-reactivity nor selectivity is predictable based on the analysis of the structures alone5.

Functions

The MART-1 / Melan-A antigen is specific for the melanocyte lineage, found in normal skin, the retina, and melanocytes, but not in other normal tissues. It is a useful as a marker for melanocytic tumors (melanomas). MART-1 / Melan-A represents an attractive candidate for generic immunotherapy of HLA-A*0201 melanoma patients. A superagonist variant of the nonameric Melan-A27–35 peptide has been shown to elicit an enhanced anti-melanoma CD8+CTL response. Clinical trials have been undertaken for peptide vaccination using the decameric analog Melan-A26–35A27L (ELAGIGILTV). In addition to exhibiting improved HLA-A*0201 binding properties (higher affinity and more stable HLA-A*0201/ peptide complexes), Melan-A26–35A27L displays more potent antigenicity and immunogenicity than the natural Melan-A peptides. A large majority of CTL raised either in vitro or in vivo against Melan-A26–35A27L are fully cross-reactive with the Melan-A parental peptide sequences and able to specifically lyse Melan-A-expressing tumor cells 6, 7. Protease-resistant, nonnatural tumor antigen derivatives are highly immunogenic and potent activators of melanoma-specific CTL. They represent promising new tools for molecular anti-melanoma immunotherapy.

References

1. Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, Miki T, Rosenberg SA (1994). Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. PNAS., 91(9) 3515-3519.

2. Coulie PG, Brichard V, Van Pel A, Wolfel T, Schneider J, Traversari C, Mattei S, De Plaen E, Lurquin C, Szikora JP, Renauld JC, Boon T (1994). A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med.,180(1):35-42.

3. Hofbauer GF, Kamarashev J, Geertsen R, Boni R, Dummer R (1998). Melan A/MART-1 immunoreactivity in formalin-fixed paraffin-embedded primary and metastatic melanoma: frequency and distribution. Melanoma Res., 8(4): 337-343.

4. Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR Appella E, Rosenberg SA (1994). Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J. Expt. Med., 180: 347–352.

5. Borbulevych OY, Insaidoo FK, Baxter TK, Powell DJ Jr, Johnson LA, Restifo NP, Baker BM (2007).  Structures of MART-126/27–35 Peptide/HLA-A2 Complexes Reveal a Remarkable Disconnect between Antigen Structural Homology and T Cell Recognition Mol. Biol.  372(5):1123–1136.

6. Valmori D, Fonteneau JF, Lizana CM, Gervois N, Lienard D, Rimoldi D, Jongeneel V, Jotereau F, Cerottini JC, Romero P(1998). Enhanced generation of specific tumor-reactive CTL in vitro by selected Melan-A/MART-1 immunodominant peptide analogues. J. Immunol., 160: 1750-1758.

7. Men Y, Miconnet I, Valmori D, Rimoldi D, Cerottini JC, Romero P (1999). Assessment of immunogenicity of human Melan-A peptide analogues in HLA-A*0201/Kb transgenic mice. J. Immunol., 162:3566-3573.